Matrix metalloproteases are a family consisting of zinc-dependent proteases whose substrates are components of extracellular matrix, and they are activated by removal of a propeptide after secretion. More than 20 members of matrix metalloproteases have been identified in human, and they are classified into collagenase (MMP-1, 8, 13), gelatinase (MMP-2, 9), stromelysin (MMP-3, 10), matrilysin (MMP-7, 26), membrane-type MMP (MMP-14, 15, 16, 17, 24, 25) according to the domain structure and substrate specificity. Overexpression of these matrix metalloproteases are observed in various cancer cells, and it is considered to be involved in the proliferation and metastasis thereof. Anticancer agents that inhibit matrix metalloprotease have been developed up to now (Non-Patent Document 1).
Matrix metalloprotease inhibitors have been developed as a therapeutic agent for rheumatoid arthritis and osteoarthritis. The articular cartilage is composed of a cartilage type II collagen network in which cartilage proteoglycans such as aggrecan and hyaluronic acid are retained. Matrix metalloprotease participates in one maintenance of the extracellular matrix. When matrix metalloprotease and TIMP (tissue inhibitor of metalloproteinases), an endogenous inhibitor thereof, are not in balance and matrix metalloprotease becomes excessively present, destruction of the cartilages and bones may progress, Particularly when collagen fibers are damaged, the joints suffer from progressive destruction as observed in rheumatoid arthritis and osteoarthritis. Accordingly, long-term suppression of the progress of joint destruction in rheumatoid arthritis and osteoarthritis can be expected by inhibiting excessive matrix metalloprotease (Non-Patent Document 2).
In osteoarthritis, the production of interleukin-1 (IL-1) and tumor necrosis factor (TNF) α also increases and extracellular matrix is degraded. The production of matrix metalloprotease is further increased by degradation products of type II collagen and fibronectin, leading to progress in degradation of matrix in the joints. When this damage of matrix exceeds a certain threshold, character of cartilage cells pathological change, and joint destruction keeps progressing. It is MMP-13 that plays a dominant role in this cleavage of type II collagen (Non-Patent Document 3).    Non-Patent Document 1: Current Oncology Reports, Vol. 6, page 96-102, 2004    Non-Patent Document 2: Annals of the Rheumatic Diseases, Vol. 60, page 62-67, 2001    Non-Patent Document 3: Biochemical Society Symposia, Vol. 70, page 115-123, 2003